Lesch-Hyhan disease (LND) is an X-linked genetic disorder that may provide a model for understanding how a single gene mutation leads to a complex behavioral phenotype. This disorder, which is the most severe form of HPRT deficiency, has attracted considerable scientific interest due to its unusual behavioral features; the best known of these is compulsive self-injurious behavior, a behavior that may allow LND to serve as a model for understanding the phenomenon of self- mutilation. However, the behavioral phenotype in LND is more extensive than this single behavior and neither the nature nor the extent of cognitive dysfunction have yet been determined. Moreover, the relationship of the specific genetic mutations that lead to HPRT deficiency and to the neurobiologic consequences of this enzyme deficiency remain poorly understood. Our overall goal in this project is threefold: 1) to quantitate the three main features of the Lesch-Nyhan behavioral phenotype (neurologic, cognitive, and behavioral, 2) to correlate them with genetic, biochemical and neuroanatomic consequences across the entire spectrum of HPRT deficiency, and 3) to investigate the dopaminerfic innervation and organization of the striatum in an HPRT deficient mouse. One outcome of this research will be a systematic analysis of the gene/behavior relationship utilizing a fully delineated LND behavioral phenotype. In Specific Aim I we will measure genetic, neurochemical, and neuroanatomical markers of HPRT deficiencyi. In Specific Aim II we will determine neurological, behavioral, and cognitive characteristics of individuals with HPRT deficiency and relate them to the finding from our first specific aim. In Specific Aim II we will utilize an HPRT-deficient mouse mutant to determine the organization and neurochemistry of the striatum at various ages during the developmental period. Specific Aims I and II will provide the first comprehensive assessment of the impact of HPRT deficiency across its full range on neurobiological markers and neurologic/cognitive/behavioral functions. Specific Aim III will establish the utility of an HPRT-deficient animal model to elucidate key developmental questions. By determining the consequences of the mutation in the HPRT gene on several levels of behavioral organization it is expected that this research will lead to new directions in understanding the pathophysiologic mechanisms involved and to better treatments. The gene sequencing and measurement of HPRT levels will be carried out in the laboratory of Dr. William Nyhan in San Diego.